RS56181B1 - PERIPHERALLY OPIOID UNITS - Google Patents

Description

Description

RELATED APPLICATION

[0001] This application has priority over US Provisional Application No. 61/502,721, filed on June 29, 2011.

TECHNICAL FIELD

[0002] This invention relates to peripherally acting opioid compounds useful as opioid receptor modulators.

BASIS OF THE INVENTION

[0003] Opiates have been the subject of intense research since the isolation of morphine in 1805, and thousands of compounds have been identified that have opiate or opiate-like activity. Many compounds interacting with the opioid receptor including those used to produce analgesia (eg, morphine) and those used to treat drug addiction (eg, naltrexone) have been used in human therapy. Almost all therapeutically useful opioids in the benzomorphan and morphinan classes have a phenolic hydroxyl group (OH) at a position that is numbered "8" in the numbering system used for 2,6-methane-3-benzazocines [eg, cyclazocine and EKC (ethylketocyclazocine)] and that is numbered "3" in the numbering system used for morphinans (eg, morphine). When the 3-hydroxyl group is replaced by a number of small, polar, neutral residues, such as carboxamide and thiocarboxamide groups, the adjacent 4-position can be substituted with a hydroxyl to produce compounds with high affinity for the opioid receptor. (Wentland M: WO 2009023567; WO 2010011619; US 6784187; US 6887998; US 7262298; US 7557119). Compounds that bind to such receptors are likely to be useful in treating diseases modulated through opiate receptors, for example, mediating analgesia, combating drug and opioid addiction, alcohol addiction, drug overdose, mental illness, compulsive behavior, bladder dysfunction, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, peripherally mediated and neuropathic pain, cough, convulsions, pulmonary edema, diarrhea, constipation, pruritus, cardiac disorders, cardioprotection, cognitive, respiratory depression, irritable bowel syndrome and gastrointestinal disorders, immunomodulation, obsessive overeating, anorexia, hyperalgesia, dyskinesia, weight gain induced by anti-psychotics and as anti-tumor agents.

[0004] The potent antinociceptive activities of classical opioids such as morphine have traditionally been considered to be predominantly mediated centrally via activity at the supraspinal or spinal level. It has also been shown that antinociceptive effects result after local administration of opioids to the periphery, for example, in the "mouse curl", and in rat models of inflammation and neuropathic pain. These effects have been attributed to opioid-induced activities mediated through peripheral opioid receptors. Neuroanatomical, molecular, and electrophysiological studies have shown that such receptors are expressed at the peripheral ends of sensory neurons where they can modulate both afferent and efferent neuronal functions, resulting in antinociception. (Furst et al. J Pharmacol Exp Ther. 2005 312(2), 609-18.). In addition, opioid receptors have been found on immune cells known to migrate into enteric tissues and epithelial cells lining the gastrointestinal tract. As such, opioids that interact with peripheral opioid receptors without crossing the blood-brain barrier could be used as potent analgesics and those without centrally mediated side effects are of interest in the treatment of opioid-mediated diseases.

SUMMARY

[0005] The invention relates to compounds of formula I or their pharmaceutically acceptable ester:

[0006] where:

u is 0, 1 or 2;

t is 0, 1, 2, 3, 4, 5, 6 or 7;

X is S or O;

R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

Each R2, R3, R4, R6, R8 and R11 is independently selected from absent, hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or

alternatively R2 and R3 together with the carbon to which they are attached to form a C=X group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or C=CH2 group;

wherein each R 20 and R 21 are independently selected from absent, hydrogen, halogen, -alkyl, substituted alkyl, aryl or substituted aryl;

R 7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; and R 10 is selected from substituted aryl in Table A.

[0007] The invention further relates to a compound for use in a method for treating a disease or disorder by modulating the activity of an opioid receptor comprising the step of administering a compound of formula I to a subject in need thereof.

PICTURE DESCRIPTION:

[0008] The above and other objects, features and advantages of the invention will be apparent from the following specific description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters designate the same parts in different views. The drawings are not necessarily to scale, instead the emphasis is on illustrating the principles of the invention.

FIG. 1: Application (intra-plantar) of compound 4 produced a dose-dependent reversal of CFA-induced weight-bearing deficits at 3, 10 and 30 μg/paw.

FIG. 2: Application of (intra-plantar) morphine-induced dose-dependent reversal of CFA-induced weight-bearing deficits at 3, 10 and 30 μg/paw.

FIG. 3: The antinociceptive properties of subcutaneous (SC) administration of compound 4 were evaluated at doses of 10, 30 and 100 μg/kg in the rat hot plate antinociception test.

FIG. 4: Subcutaneous administration of compound 4 produced a dose-dependent reversion of formalin-induced events in the formalin model of pain.

FIG. 5: Administration of (intraperitoneal) compound 4 blocked acetic acid-induced writhing in a dose-dependent manner in an acetic acid-induced writhing model of inflammatory pain.

DETAILED DESCRIPTION

[0009] In one exemplary embodiment, the invention relates to a compound of formula I or a pharmaceutically acceptable ester thereof:

[0010] where:

u is 0, 1 or 2;

t is 0, 1, 2, 3, 4, 5, 6 or 7;

X is S or O;

<R>1< is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or >substituted heterocyclyl;

Each R2, R3, R4, R6, R8 and R11 is independently selected from absent, hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively R2 and R3 together with the carbon to which they are attached form a C=X group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or C=CH2 group;

wherein each R 20 and R 21 are independently selected from absent, hydrogen, halogen, -alkyl, substituted alkyl, aryl or substituted aryl;

R 7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl;

R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl;

R10 is selected from Table A:

TABLE A

[0011] Where s is 0, 1, 2 or 3;

p is 0, 1, 2, 3, 4, 5, 6 or 7;

q is 0, 1, 2, 3, 4 or 5;

[0012] Each R100, R101, R102, R103, R104, and R105 is independently selected from hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; and wherein the term "substituted" means the replacement of one or more hydrogen radicals in a given structure with a radical of an indicated substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyl, aminocarbonyl, Alkylaminocarbonyl, Arylaminocarbonyl, Alkoxycarbonyl, Aryloxycarbonyl, Haloalkyl, Amino, Trifluoromethyl, Cyano, Nitro, Alkylamino, Arylamino, Alkylaminoalkyl, Arylaminoalkyl, Aminoalkylamino, Hydroxy, Alkoxyalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aminocarbonylalkyl, Acyl, Aralkoxycarbonyl, Carboxylic acid, Sulfonic acid, Sulfonyl, Phosphonic acid acids, aryl, heteroaryl, heterocyclic and aliphatic.

[0013] In a preferred embodiment, R<7> is hydrogen.

[0014] In a preferred embodiment, u is 1.

[0015] In a preferred embodiment, X is oxygen.

In a preferred embodiment, the invention relates to a compound of formula V or a pharmaceutically acceptable ester thereof:

[0017] In a preferred embodiment, R1 is selected from -(CH2)a-c-C3H5, -(CH2)a-c-C4H7,-(CH2)a-C-C5H9, -(CH2)a-CH=CH2, -CH3, -CH2-CH2-phenyl or -(CH2)a-CH=C(CH3)2 where a is independently 0, 1, 2 or 3.

[0018] In a preferred embodiment, R 4 is hydrogen or hydroxyl.

[0019] In a preferred embodiment, R 9 is hydrogen.

[0020] The invention further relates to a compound of formula I as defined in the preceding text for use in a process for the treatment of a disease or disorder selected from pain, drug addiction, opiate addiction, alcohol addiction, nicotine addiction, cocaine addiction, post-operative ileus, pruritus, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, cough and hyperalgesia.

[0021] In a preferred embodiment, the invention relates to a compound or a pharmaceutically acceptable ester thereof, selected from Table B:

TABLE B

[0022] In a preferred embodiment, the invention relates to a compound selected from Table B, where R 10 is selected from Table A and R 9 is hydrogen.

[0023] In a preferred embodiment, the invention relates to a compound selected from Table C or its pharmaceutically acceptable ester, whereby compound no. 1 is the reference compound:

TABLE C

[0024] In a more preferred embodiment, the invention relates to a compound for use in a method of treating an opioid receptor mediated disease or disorder comprising the step of administering a compound of Table C to a subject in need thereof. In one exemplary embodiment, the invention relates to a use in the treatment of pain comprising administering a compound of formula I to a subject in need thereof. In one example embodiment, the pain is selected from inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural pain, cancer pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic headache pain, chronic pain from neuropathic conditions, chronic pain from post-stroke conditions and chronic migraine pain. In one exemplary embodiment, the pain is associated with osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burns, sunburn, snake bite, spider bite, insect bite, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, pruritus, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, post-amputation stump pain, phantom limb pain, post-operative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, meralgia paresthetica, burning mouth syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, Vidian neuralgia, inflammatory bowel disease, irritable bowel syndrome, sinus headache, tension headache, childbirth, child birth, menstrual pain and cancer.

[0025] In one exemplary embodiment, the invention relates to a compound for use in the treatment of pain associated with arthritis. In one exemplary embodiment, the arthritis is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis.

[0026] The compounds of this application show good binding affinities for opiate receptors. Some of the compounds of the invention exhibit agonistic activity based on their ability to induce GTPγS binding at one or more opiate receptors (MOR, DOR, KOR or NOP). As such, the compounds of this application are useful in the treatment of diseases modulated through opioid receptor activation; for example: through the mediation of analgesia, the fight against drug and opioid addiction, alcohol addiction, drug overdose, mental illness, bladder dysfunction, neurogenic bladder, interstitial cystitis, urinary incontinence, premature ejaculation, inflammatory pain, neuropathic pain, cough, pulmonary edema, diarrhea, pruritus, cardiac disorders, cardioprotection and cognitive, respiratory depression, irritable bowel syndrome and gastro-intestinal disorders, immunomodulation and as anti-tumor agents.

[0027] The compounds according to the present invention can be used in methods for the treatment of diseases where binding of the ligand primarily to the μ opioid receptor is desired. Compounds of interest can also bind to κ and δ receptors. Opioid receptors can be located outside the central nervous system in the periphery and located on nerve cells, immune cells, glial cells or epithelial cells. If the compounds were directly injected into the central nervous system (CNS) they would bind to opioid receptors in the central nervous system.

[0028] In one exemplary embodiment, the compounds are opioid receptor agonists. In the following exemplary embodiment, the compounds are opioid antagonists that prevent or treat a condition or disease caused by an opioid (either endogenous or exogenous). In the following exemplary embodiment, the compounds may function broadly in modulating opioid receptor activity because they have a combination of agonistic and antagonistic properties at μ, κ and δ receptors. In the following embodiment, the compounds according to the invention preferably do not significantly cross the blood-brain barrier.

[0029] The compounds according to the present invention can be used in methods for antagonizing opioid receptors, especially where undesirable symptoms or conditions are side effects of the administration of exogenous opioids. In addition, the compounds of the invention may be used to treat patients having disease states that are ameliorated by binding to opioid receptors or in any treatment where temporary suppression or modulation of m opioid receptor signaling is desired.

[0030] Such symptoms, conditions or diseases include complete or partial antagonism of opioid-induced sedation, confusion, respiratory depression, euphoria, dysphoria, hallucinations, pruritus (itching), increased gallbladder tone, increased gallbladder colic and urinary retention, ileus, emesis and addiction; prevention or treatment of opioid and cocaine addiction; rapid detoxification from opioids; treatment of alcoholism; treatment of alcoholic coma; detection of opioid use or abuse (pupil test); treatment of eating disorders; obesity treatment; treatment of post-concussion syndrome; supplementary therapy in septic, hypovolemic or endotoxin-induced shock; potentiation of opioid analgesia (especially at ultra-low doses); reversal or prevention of opioid tolerance and physical dependence (especially at ultra-low doses); prevention of sudden infant death syndrome); treatment of dyskinesia; treatment of metabolic diseases, including type 1 and 2 diabetes; treatment of the endocrine system (including increased release of luteinizing hormone, treatment of infertility, increasing number of multiple births in livestock, and male and female sexual behavior); treatment of the immune system and cancers associated with opioid receptor binding; treatment of anxiolysis; treatment of diuresis; treatment and regulation of blood pressure; treatment of tinnitus or impaired hearing; treatment of epilepsy; treatment of cachexia; treatment of general cognitive dysfunctions; and treatment of kleptomania.

[0031] The compounds according to the present invention can also be used as cytostatic agents, as antimigraine agents, as immunomodulators, as immunosuppressants, as antiarthritic agents, as antiallergic agents, as virucides, for the treatment of diarrhea, as antischizophrenics, as uropathic agents, as antitussive agents, as anti-addiction agents, as anti-smoking agents, for the treatment of alcoholism, as hypotensive agents, for the treatment and/or prevention of paralysis resulting from traumatic ischemia, for general neuroprotection against ischemic trauma, as supplements for the treatment of hyperalgesia and nerve transplants with growth factor, as anti-diuretics, as stimulants, as anti-convulsants, or for the treatment of obesity. In addition, the subject compounds may be used in the treatment of Parkinson's disease as an adjunct to L-dopa to treat dyskinesia associated with L-dopa treatment.

[0032] In certain embodiments, compounds according to the invention can be used in procedures for the prevention or treatment of gastrointestinal dysfunction including, but not limited to, irritable bowel syndrome, opioid-intestinal dysfunction, colitis, postoperative and opioid-induced emesis (nausea and vomiting), reduced gastric motility and emptying, inhibition of small and/or large intestinal propulsion, increased amplitude of non-propulsive segmental contractions, constriction Sphincter of Oddi, increased anal sphincter tone, impaired reflex relaxation with rectal distension, decreased gastric, gallbladder, pancreatic, or intestinal secretions, increased absorption of water from intestinal contents, gastroesophageal reflux, gastroparesis, cramps, bloating, abdominal or epigastric pain and discomfort, constipation, and delayed absorption of orally administered drugs or nutrients.

[0033] In one exemplary embodiment, the compositions according to the invention may additionally contain one or more compounds that may be designed to increase the analgesic potency of opioids and/or to reduce the development of analgesic tolerance. Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao, M. J. et al., Pain, 1996, 67, 361), L-364,718 and other CCK antagonists (Dourish, C. T. et al., Eur. J. Pharmacol., 1988, 147, 469), NOS inhibitors (Bhargava, H. N. et al., Neuropeptides, 1996, 30, 219), PKC inhibitors (Bilsky, E. J. et al., J. Pharmacol. Exp. Ther., 1996, 277, 484) and dynorphin antagonists or antisera (Nichols, M. L. et al., Pain, 1997, 69, 317). The descriptions of each of the above documents are incorporated herein by reference in their entirety.

[0034] In one exemplary embodiment, the compounds of the invention may be used in methods for the prevention or treatment of postoperative or opioid-induced ileus. In another exemplary embodiment, the compounds according to the invention can be used as analgesics, anesthetics, anti-pruritic, anti-diarrheal, anti-convulsant, anti-cough and/or anorexic.

Definitions

[0035] In the following text definitions of various terms used to describe this invention are given. These definitions refer to terms as used in this specification and claims, unless otherwise limited in specific cases, either individually or as part of a larger group.

[0036] The term "aliphatic group" or "aliphatic" means a non-aromatic moiety that may be saturated (eg, a single bond) or contain one or more units of unsaturation, eg, double and/or triple bonds. The aliphatic group may be straight-chain, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.

[0037] In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines and polyimines, for example. Such aliphatic groups may be additionally substituted. It is understood that aliphatic groups may include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and substituted or unsubstituted cycloalkyl groups as defined herein.

[0038] The term "acyl" means hydrogen-substituted carbonyl, alkyl, partially saturated or fully saturated cycloalkyl, partially saturated or fully saturated heterocycle, aryl or heteroaryl. For example, acyl includes groups such as (C1-C6)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3-C6)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (eg, benzoyl), and heteroaroyl (eg, thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl, furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl, etc.). benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl portion of the acyl group may be any of the groups described in the respective definitions. When designated as "optionally substituted," the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition of "substituted" or the alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl portion of the acyl group may be substituted as described in the preferred and more preferred list above. of substituents, respectively.

[0039] The term "alkyl" is defined to include branched and straight chain, substituted or unsubstituted saturated aliphatic hydrocarbon radicals/groups having the indicated number of carbons. Preferred alkyl groups contain from about 1 to about 24 carbon atoms ("C1-C24"). Other preferred alkyl groups contain about 1 to about 8 carbon atoms ("C1-C8") such as about 1 to about 6 carbon atoms ("C1-C6"), or such as about 1 to about 3 carbon atoms ("C1-C3"). Examples of C 1 -C 6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl radicals.

[0040] The term "alkenyl" refers to linear or branched radicals having at least one carbon-carbon double bond. Such radicals preferably contain from about two to about twenty-four carbon atoms ("C2-C24"). Other preferred alkenyl radicals are "lower alkenyl" radicals having two to about ten carbon atoms ("C2-C10") such as ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred lower alkenyl radicals comprise 2 to about 6 carbon atoms ("C2-C6"). The terms "alkenyl", and "lower alkenyl", include radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

[0041] The term "alkynyl" means linear or branched radicals having at least one carbon-carbon triple bond. Such radicals preferably contain from about two to about twenty-four carbon atoms ("C2-C24"). Other preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms such as propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferred lower alkynyl radicals comprise 2 to about 6 carbon atoms ("C2-C6").

[0042] The term "cycloalkyl" refers to saturated carbocyclic radicals having three to about twelve carbon atoms ("C3-C12"). The term "cycloalkyl" includes saturated carbocyclic radicals having three to about twelve carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0043] The term "cycloalkenyl" refers to partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals which are partially unsaturated carbocyclic radicals containing two double bonds (which may or may not be conjugated) may be designated as "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0044] The term "alkylene," as used herein, means a divalent group derived from a linear or branched saturated hydrocarbon chain having the indicated number of carbon atoms. Examples of alkylene groups include, but are not limited to, ethylene, propylene, butylene, 3-methyl-pentylene, and 5-ethyl-hexylene.

[0045] The term "alkenolene," as used herein, means a divalent group derived from a linear or branched hydrocarbon moiety containing the indicated number of carbon atoms having at least one carbon-carbon double bond. Alkenylene groups include, but are not limited to, for example, ethenylene, 2-propenylene, 2-butenylene, 1-methyl-2-buten-1-ylene, and the like.

[0046] The term "alkynylene," as used herein, means a divalent group derived from a linear or branched hydrocarbon moiety containing the indicated number of carbon atoms having at least one carbon-carbon triple bond. Representative alkynylene groups include, but are not limited to, for example, propynylene, 1-butynylene, 2-methyl-3-hexynylene, and the like.

[0047] The term "Alkoxy" refers to linear or branched oxy radicals each having alkyl moieties of one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy.

[0048] The term "Alkoxyalkyl" means alkyl radicals having one or more Alkoxy radicals attached to an Alkyl radical, that is, so as to form mono-Alkoxyalkyl and Di-Alkoxyalkyl radicals.

[0049] The term "aryl", alone or in combination, means an aromatic system containing one, two or three rings where such rings may be linked together in a pendant manner or may be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane furanyl, quinazolinyl, pyridyl and bophenyl.

[0050] The terms "heterocyclyl", "heterocycle", "heterocyclic" or "heterocyclo" refer to saturated, partially unsaturated and unsaturated ring-shaped radicals containing a heteroatom, which may also appropriately be designated as "heterocyclyl", "heterocycloalkenyl" and "heteroaryl", where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include a saturated 3- to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (eg, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); a saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, morpholinyl, etc.); a saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicals may include pentavalent nitrogen, as in tetrazolium and pyridinium radicals. The term "heterocycle" also includes radicals where heterocyclyl radicals are fused to aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene and the like.

[0051] The term "heteroaryl" refers to unsaturated aromatic heterocyclyl radicals. Examples of heteroaryl radicals include an unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg, 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; an unsaturated fused heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (eg, tetrazolo[1,5-b]pyridazinyl, etc.), etc.; an unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; an unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; an unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; an unsaturated fused heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg, benzoxazolyl, benzoxadiazolyl, etc.); an unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (eg, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; an unsaturated fused heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzothiadiazolyl, etc.) and the like.

[0052] The term "heterocycloalkyl" refers to heterocyclo-substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl" radicals having one to six carbon atoms in the heterocyclo radical.

[0053] The term "alkylthio" refers to radicals containing a linear or branched alkyl radical, from one to about ten carbon atoms attached to a divalent sulfur atom. Preferred alkylthio radicals have alkyl radicals of one to about twenty-four carbon atoms or, preferably, one to about twenty carbon atoms. More preferred alkylthio radicals have alkyl radicals which are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of about one to about eight carbon atoms. Examples of such lower alkylthio radicals include methylthio, ethylthio, propylthio, butylthio and hexylthio.

[0054] The terms "aralkyl" or "arylalkyl" refer to aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl.

[0055] The term "aryloxy" refers to aryl radicals attached via an oxygen atom to other radicals.

[0056] The terms "aralkoxy" or "arylalkoxy" refer to aralkyl radicals bonded through an oxygen atom to other radicals.

[0057] The term "aminoalkyl" refers to alkyl radicals substituted with amino radicals. Preferred aminoalkyl radicals have alkyl radicals having about one to about twenty-four carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl" having alkyl radicals having one to about ten carbon atoms. Most preferred are aminoalkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl and the like.

[0058] The term "alkylamino" means amino groups which are substituted with one or two alkyl radicals. Preferred alkylamino radicals include alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino" having alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl radicals having one to about eight carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like.

[0059] The term "substituted" means the replacement of one or more hydrogen radicals in a given structure with a radical of an indicated substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyl, aminocarbonyl, Alkylaminocarbonyl, Arylaminocarbonyl, Alkoxycarbonyl, Aryloxycarbonyl, Haloalkyl, Amino, Trifluoromethyl, Cyano, Nitro, Alkylamino, Arylamino, Alkylaminoalkyl, Arylaminoalkyl, Aminoalkylamino, Hydroxy, Alkoxyalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aminocarbonylalkyl, Acyl, Aralkoxycarbonyl, Carboxylic acid, Sulfonic acid, Sulfonyl, Phosphonic acid, aryl, heteroaryl, heterocyclic and aliphatic. It is understood that the substituent may be additionally substituted.

[0060] For simplicity, the chemical moieties defined and recited may be monovalent chemical moieties (eg, alkyl, aryl, etc.) or multivalent moieties under appropriate structural circumstances apparent to those skilled in the art. For example, an "alkyl" moiety may be designated as a monovalent radical (eg, CH3-CH2-), or in other cases, a divalent linking group may be "alkyl," in which case one skilled in the art will understand that alkyl is a divalent radical (eg, -CH2-CH2-), which is equivalent to the term "alkylene." Similarly, in circumstances where divalent moieties are required and denoted as "alkoxy", "alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic", "alkyl" "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl", those skilled in the art will understand that the terms "alkoxy", "alkylamino", "aryloxy", "alkylthio", "aryl", "heteroaryl", "heterocyclic", "alkyl", "alkenyl", "alkynyl", "aliphatic", or "cycloalkyl" means the corresponding divalent moiety.

[0061] The terms "compound," "drug," and "prodrug" as used herein all include pharmaceutically acceptable salts, cocrystals, solvates, hydrates, polymorphs, enantiomers, diastereomers, racemates, and the like of compounds, drugs, and prodrugs having formulas as shown herein.

[0062] Substituents designated as attached via variable attachment points may be attached to any available position on the ring structure.

[0063] As used herein, the term "effective amount" in connection with a subject treatment method, means an amount of a subject compound which, when administered as part of a desired dosage regimen, brings the management of the disease or disorder to a clinically acceptable standard.

[0064] It will be understood that in various embodiments of the invention, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl and heterocycloalkyl are intended to be monovalent or divalent. Thus, alkylene, alkenylene and alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, arylalkylene, heteroarylalkylene and heterocycloalkylene groups are included in the above definitions, and are applicable to provide the formulas given herein with the appropriate valency.

[0065] The terms "halo" and "halogen," as used herein, refer to an atom selected from fluorine, chlorine, bromine, and iodine.

[0066] The compounds described herein contain one or more asymmetric centers and thus give enantiomers, diastereomers and other stereoisomeric forms which can be defined, according to absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for aminooxyelines. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers can be prepared from their respective optically active precursors by the procedures described herein, or by resolution of racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques, which are known to those skilled in the art. Additional details regarding the separations can be found in Jacques, et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise indicated, the compounds are intended to include the E and Z geometric isomers. Similarly, all tautomeric forms are also designated as included. The configuration of any carbon-olefin double bond appearing herein is chosen for convenience only and is not intended to indicate a particular configuration unless the text so directs; thus the carbon-carbon double bond shown here arbitrarily as trans may be cis, trans, or a mixture of the two in any proportion.

[0067] The term "subject" as used herein refers to a mammal. Subject therefore means, for example, dogs, cats, horses, cows, pigs, guinea pigs, and the like. Preferably the subject is a human. When the subject is human, the subject may be referred to herein as a patient.

[0068] As used herein, the term "pharmaceutically acceptable salt" means those salts of compounds formed by the method of the present invention which, within the scope of rational medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0069] Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds according to the invention, or in particular by reaction of the functional group of the free base with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts, e.g., salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali or alkaline earth metal salts include salts of sodium, lithium, potassium, calcium, magnesium and the like. Additional pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium, and amino cations formed using counterions such as halide, hydroxy, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate, and aryl sulfonate.

[0070] The compounds of the present invention may be modified by the addition of various functional groups via the synthetic means described herein to enhance selective biological properties. Such modifications include those that increase biopenetration into a given biological system (eg, blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism, and alter the rate of excretion. Combinations of substituents and variables contemplated by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, means compounds that possess stability sufficient to permit manufacture and that maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (eg, therapeutic or prophylactic administration to a subject).

[0071] The synthesized compounds can be separated from the reaction mixture and further purified using a procedure such as column chromatography, high pressure liquid chromatography or recrystallization. In addition, the various synthetic steps can be performed in an alternating or sequential order to obtain the desired compounds. Additionally, the solvents, temperatures, reaction times, etc., described herein are for illustrative purposes only and variations in the reaction conditions may produce the desired bridged macrocyclic products of the present invention. Synthetic chemical transformations and protecting group (protection and deprotection) methodologies useful in synthesizing the compounds described herein include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995).

[0072] The term "hydroxy protecting group," as used herein, refers to a sensitive chemical moiety known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure(s), the hydroxy protecting group as described herein can be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G., S.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl, paramethoxybenzyldiphenylmethyl, triphenylmethyl, tetrahydrofuran, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, paratoluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl and the like. Preferred hydroxy protecting groups for the present invention are acetyl (Ac or -C(O)CH 3 ), benzoyl (Bz or -C(O)C 6 H 5 ) and trimethylsilyl (TMS or -Si(CH 3 ) 3 ).

[0073] The term "amino protecting group," as used herein, refers to a sensitive chemical moiety known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s), the amino protecting group as described herein can be selectively removed. Amino protecting groups as known are generally described in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and the like.

[0074] As used herein, the term "pharmaceutically acceptable ester" refers to esters of compounds formed by the process of the present invention that hydrolyze in vivo and include those that readily break down in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanic and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of certain esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates.

[0075] The term "pharmaceutically acceptable prodrugs" as used herein means those prodrugs of the compounds formed by the process of the present invention which, within the scope of rational medical judgment, are suitable for use in contact with the tissues of humans and lower animals with unnecessary toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as zwitterionic forms, where possible, of the compounds according to subject invention. "Prodrug", as used herein, means a compound which can be translated in vivo by metabolic means (eg, hydrolysis) to produce any compound described by the formulas of this invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0076] The term "acyl" includes residues derived from acids, including but not limited to carboxylic acids, carbamic acids, carboxylic acids, sulfonic acids, and phosphoric acids. Examples include aliphatic carbonyls, aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphatic sulfinyls, aromatic phosphates, and aliphatic phosphates. Examples of aliphatic carbonyls include, but are not limited to, acetyl, propionyl, 2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

[0077] The term "aprotic solvent," as used herein, refers to a solvent that is relatively inert to proton activity, ie, does not act as a proton donor. Examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N-methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on such factors as reagent solubility, reagent reactivity, and preferred temperature ranges, for example. Additional considerations of apotonic solvents can be found in textbooks of organic chemistry or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

[0078] The terms "protogenic organic solvent" or "protic solvent" as used herein refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol and the like. Such solvents are well known to those skilled in the art, and individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as reagent solubility, reagent reactivity, and preferred temperature ranges, for example. Additional discussions of protogenic solvents can be found in textbooks of organic chemistry or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986.

PHARMACEUTICAL COMPOSITIONS

[0079] Pharmaceutical compositions according to the present invention contain a therapeutically effective amount of a compound according to the present invention formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation excipient of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talcum powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; sunflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline solution; Ringer's solution; ethyl alcohol, and phosphate buffered solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, at the discretion of the formulator. The pharmaceutical compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), buccally, or as an oral or nasal spray.

[0080] The pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir, preferably by oral or injection administration. The pharmaceutical compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carriers, adjuvants or excipients. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its administration form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0081] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, germ oil, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of fatty acids and sorbitan and their mixtures. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0082] Injectable preparations, for example, sterile injectable aqueous or oily suspensions can be formulated according to the known state of the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable carriers and solvents that may be used are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fatty oils have conventionally been used as a solvent or suspending medium. For this purpose any light fatty oil can be used including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have been used in the preparation of injectable preparations.

Injectable formulations may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0084] In order to prolong the effect of the drug, it is often desirable to slow down the absorption of the drug from the injection site. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its dissolution rate, which, in turn, can depend on crystal size and crystal shape. Alternatively, delayed absorption of a parenterally administered drug has been achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot forms are prepared by forming microencapsulating matrices of the drug in biodegradable polymers such as polylactide or polylactide-co-glycolide. Depending on the drug to polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations have also been prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0085] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or wax for suppositories which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0086] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binding agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia; c) humectants such as glycerol; d) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) agents that slow dissolution such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0087] In one exemplary embodiment, the administration of microparticles containing iloprost or another pharmaceutical agent for administration in addition to iloprost provides local or plasma concentrations maintained at approximately constant values during the intended release period (eg, up to 2 to 24 hours, to allow dosing once, twice, three times, four times, or more than four times a day). Microparticle formulations may allow patients to take treatment less frequently, and to obtain longer and more stable relief.

[0088] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0089] The active compounds can also be in micro-encapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as gastro-resistant coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as in normal practice, additional substances other than inert diluents, eg, tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may also optionally contain opacifying agents and may also be formulated to release only the active ingredient(s), or preferably, to a specific portion of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as may be required. Ophthalmic formulation, eye drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Ointments, pastes, creams and gels may contain, in addition to the active compound according to this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or their mixtures.

[0092] Powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain common propellants such as chlorofluorocarbons.

[0093] Transdermal patches have the added advantage of providing controlled delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of compounds through the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0094] The total daily dose of a compound of the present invention administered to a subject in single or divided doses may be in amounts, for example, from 0.01 to 50 mg/kg body weight or more typically from 0.1 to 25 mg/kg body weight. Single-dose compositions may contain such amounts or such amounts divided into smaller portions to make a daily dose. In general, treatment regimens of the present invention comprise administering to a patient in need of such treatment from about 1 mg to about 200 mg of a compound (one or more) of the present invention per day or weekly or biweekly in single or multiple doses.

[0095] Dosage regimens may be adjusted to provide an optimal therapeutic response. For example, the administration may be once to three times a day over a period of one day to several days, weeks, months and even years, and may even be for the lifetime of the patient. Practically speaking, a unit dose of any given composition of the invention or active agent may be administered in a variety of dosage regimens, depending on the judgment of the physician, the needs of the patient, and so on. The specific dosage regimen will be known to those skilled in the art or may be determined experimentally using routine procedures. Examples of dosage regimens include, without limitation, administration five times a day, four times a day, three times a day, twice a day, once a day, every other day, three times a week, twice a week, once a week, twice a month, once a month, and so on.

[0096] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly known to one skilled in the art.

EXAMPLES

[0097] The compounds and methods of the present invention will be understood in connection with the following examples, which are intended to be illustrative only and not to limit the scope of the invention.

Various changes and modifications of the described exemplary embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to chemical structures, substituents, derivatives, formulations and/or processes according to the invention may be made without departing from the spirit of the invention and the scope of the appended claims.

[0098] Although the invention has been described in connection with various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will understand that variations and modifications can be made that are within the spirit of the invention and the scope of the appended claims.

[0099] The morphinan compounds of the present invention can be synthesized using procedures described, for example, in US Pat. no. 5,250,542, US Pat. no. 5,434,171, US Pat. no. 5,159,081, and US Pat. no. 5,270,328. The optically active and commercially available naltrexone which can be used as a starting material in the synthesis of some of the compounds of the invention can be prepared by the general procedure described in US Pat. No. 3,332,950.

[0100] Various changes and modifications of the described exemplary embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those related to chemical structures, substituents, derivatives, formulations and/or processes according to the invention may be made without departing from the scope of the appended claims.

SYNTHESIS OF HETEROCYCLIC BI-ARYLS

Example 1: Synthesis of tert-butyl 4-bromophenethylcarbamate

[0101]

[0102] Bromophenethylamine (50 g, 250 mmol) and triethylamine (105 mL, 750 mmol) were stirred in dichloromethane (DCM; 1.5 L), and cooled to 0°C. Boc anhydride (82 g, 375 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water (1 L), brine (500 mL), dried (MgSO4) and concentrated to give an orange oil. The crude residue was crystallized from hexane (250 mL) to give a white solid, tert-butyl 4-bromophenethylcarbamate (39.85 g, 133 mmol, 53 %).

Example 2: Synthesis of tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate

[0103] Industrial methylated spirits (IMS; 15 mL) and water (5 mL) were thoroughly degassed. Tert-butyl 4-bromophenethylcarbamate (1.08 g, 3.63 mmol), sodium carbonate (1.54 g, 14.52 mmol), palladium tetrakis (0.42 g, 0.36 mmol) and 2,4-dimethoxy-5-pyrimidinylboronic acid (1.00 g, 5.44 mmol) were added and the reaction mixture was heated to 90°C for 18 hours. No starting material was recorded by LCMS. Water (100 ml) and ethyl acetate (300 ml) were added and the organic layer was separated. The organic layer was washed with water (100 mL), dried (MgSO 4 ) and concentrated to give a yellow oil. The crude residue was subjected to column chromatography (20 to 60% ethyl acetate/hexane) to give a yellow oil, tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate, which crystallized on standing (1.18 g, 3.28 mmol, 91%).

Example 3: Synthesis of 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride

[0104] An aqueous solution of hydrochloric acid (6 M, 15 mL) was added to tert-butyl 4-(2,4-dimethoxypyrimidin-5-yl)phenethylcarbamate (0.5 g, 1.39 mmol) and the reaction mixture was stirred at reflux for 4 hours. No starting material was recorded by LCMS. The precipitate was filtered, washed with water (5 mL) and dried under reduced pressure (50 °C) to give a light yellow solid, 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (0.32 g, 1.35 mmol, 86%).

Example 4: Synthesis of tert-Butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate

[0105] IMS (50 mL) and water (16 mL) were thoroughly degassed. Tert-butyl 4-bromophenethylcarbamate (3.52 g, 11.7 mmol), sodium carbonate (5.0 g, 46.9 mmol), palladium tetrakis (1.35 g, 1.2 mmol) and 1-benzyl-1H-pyrazole-4-boronic acid pinacol ester (5.0 g, 17.6 mmol) were added and the reaction mixture was heated to 90°C overnight. The reaction was partitioned between ethyl acetate (500 mL) and water (250 mL) and brine (250 mL), then dried (MgSO 4 ). Filtration and removal of the solvent gave a crude residue which was subjected to column chromatography (50% ethyl acetate/heptane) to give tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (4.2 g, 11.1 mmol, 95% yield).

Example 5: Synthesis of 2-(4-(1-Benzyl-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride

[0106] To tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (4.2 g, 11.1 mmol) was added HCl/dioxane (approx. 4 M, 100 mL). After 5 minutes, stirring of the reaction mixture was stopped and another 50 mL of HCl/dioxane was added. The reaction was stirred at room temperature for 6 hours. The solvent was removed under reduced pressure to give 2-(4(1-benzyl-1H-pyrazol-4-yl)phenyl)ethanamine hydrochloride as a yellow solid (4.0 g, 11.1 mmol, 100 % yield).

Example 6: Synthesis of tert-Butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate

[0107] IMS (600 mL) and water (250 mL) were thoroughly degassed. Tert-butyl 4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boric acid (25.0 g, 163 mmol) were added and the reaction mixture was heated to 90°C for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO 4 ) and concentrated to give a brown solid. The crude residue was subjected to column chromatography (0 to 1.5% MeOH in DCM) to give a white solid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (20.95 g, 63.8 mmol, 58% yield).

Example 7: Synthesis of 5-(4-(2-Aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride

[0108] To tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (10.25 g, 31.0 mmol) was added an aqueous solution of hydrochloric acid (6 M, 220 mL) and the reaction mixture was stirred at reflux overnight. The reaction was cooled to room temperature and the precipitate was filtered, washed with water (5 mL) and dried under reduced pressure (50°C). The acidic solution was concentrated under reduced pressure and the resulting solid was combined with the filtered solid to give 5-(4-(2-aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride (7.80 g, 31.0 mmol, 100% yield).

OPIOID SYNTHESIS

[0109]

Example 8: Synthesis of compound 4

[0110] To a solution of crude compound 12 (52 g) in acetic acid (1 L) at 90°C was added concentrated HCl (35 mL). To this was then added zinc powder (64g, 0.98 mol) over 35 minutes and after the addition was complete an additional portion of concentrated HCl (40 mL) was added over 5 minutes. A second portion of zinc powder (64g, 0.98 mol) was then added to the reaction mixture over 1 hour. After 30 minutes, a third portion of zinc powder (32g, 0.49 mol) was added and the reaction was heated for an additional 1 hour. The reaction was cooled to ~60°C and filtered and the residual zinc was washed with hot acetic acid. The filtrate was concentrated under reduced pressure and the residue was diluted with concentrated ammonia (1 L) and 2-methyltetrahydrofuran (1 L) and water (0.5 L). The mixture was stirred for 10 minutes and the liquids were decanted from the brown gum. The tire is washed with water and all fluids are combined. The organic phase was separated, dried over MgSO4i, combined with brown gum and concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane/methanol (8:2) and chromatographed on a short silica plug column eluting with dichloromethane/methanol (8:2) and then dichloromethane/methanol/triethylamine (16:3:1). Fractions containing the product were evaporated and subjected to column chromatography again eluting with dichloromethane/methanol (9:1) and then dichloromethane/(16% NH3/methanol) (9:1). The product obtained from this was then further purified using prep. HPLC to give compound 4; LC/MS 545 (M+H)+; NMR(DMSO-D6): 1.30-2.10 (6H, m), 2.12-3.05 (11H, m), 3.10-3.60 (2H, m), 4.04 (1H, bs), 4.58 (1H, s), 6.42 (1H, bs), 7.19 (2H, d), 7.40-7.60 (5H, m), 10.45 (3H, bs).

(Reference) Example 9: Synthesis of compounds 13 and 14

[0111]

[0112] A solution of (5a)-N-[2-(4-bromophenyl)ethyl]-14-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-3-carboxamide (1.7 g, 3.3 mmol) in denatured ethanol (15 mL) was degassed with argon for 20 min and then Na2CO3 (1.4 g, 13.3 mmol) was added. 2,4-dimethoxypyrimidin-5-ylboronic acid (0.92 g, 5.0 mmol), degassed water (5 mL), and Pd(PPh3)4 (0.38 g, 0.33 mmol). The reaction was hermetically sealed and heated in a microwave reactor at 120°C for 25 min. The reaction was concentrated to ~10 mL, diluted with dichloromethane (50 mL) and washed with water (40 mL). The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with dichloromethane to methanol/dichloromethane (1:9). The fraction containing the product was repurified on silica eluting with dichloromethane/ethyl acetate (9:1) to dichloromethane/ethyl acetate/methanol (8:1:1) to give compound 13 (1.38 g, 73%) as a yellow oil.

[0113] To a mixture of compound 13 (0.70 g, 1.2 mmol) and sodium iodide (1.33 g, 4.9 mmol) in anhydrous acetonitrile (8 mL) was added chlorotrimethylsilane (0.63 mL, 4.9 mmol) and the reaction mixture was stirred for 5 hours. The reaction mixture was diluted with 5% aqueous sodium sulfite (5 mL) and water (10 mL) and then basified with saturated aqueous sodium carbonate. This was extracted twice with dichloromethane (80 mL) and once with ethyl acetate (50 mL). The organic layers were combined and evaporated to give a yellow solid. It was partially dissolved in 2M HCl and the insoluble material was filtered off with celite. The aqueous phase was basified with saturated sodium carbonate and the resulting white solid was filtered and dried under vacuum. This was then purified on silica eluting with dichloromethane/methanol (9:1) to give compound 14 (197mg). Compound 14 was dissolved in dichloromethane (5 mL) and 4M HCl in diethyl ether (40 mL) was added.

The mixture was stirred for 2.5 hours and evaporated to give the chloride salt of compound 14 (0.21g, 29%) as a white solid; LC/MS 543 (M+H)<+>; NMR(DMSO-D6): 1.40-1.57 (2H, m), 1.90-2.01 (1H, m), 2.10-2.20 (1H, m), 2.58-2.70 (1H, m), 2.75-2.92 (5H, m), 2.92-3.15 (3H, m), 3.30-3.65 (4H, m), 5.31 (1H, s), 6.79 (1H, s), 6.93 (1H, d), 7.26 (2H, d), 7.44 (2H, d), 7.55 (1H, d), 7.60-7.70 (2H, m), 9.36 (1H, bs), 11.10 (1H, bs), 11.20 (1H, bs).

Example 10: Synthesis of Compound 10

[0114]

[0115] Oxymorphone triflate (3.0 g, 7.0 mmol) was stirred in degassed DMSO (40 mL). N-Hydroxysuccinimide (1.60 g, 13.9 mmol) was added, followed by triethylamine (1.94 mL, 13.9 mmol), palladium acetate (156 mg, 0.7 mmol), and xanthophos (402 mg, 0.7 mmol). The reaction mixture was stirred at 70°C under CO overnight. Additional palladium acetate (1.04 g, 4.61 mmol) and xanthophos (2.68 g, 4.63 mmol) were added and the reaction was heated for 6 hours at 70°C under a CO atmosphere. The mixture was allowed to return to room temperature before the addition of 4-(4-(2-aminoethyl)phenyl)pyridin-2(1H)-one hydrochloride (2.0 g, 8.0 mmol) and triethylamine (2 mL, 14.3 mmol). The reaction was stirred for 1 hour before removing the DMSO under reduced pressure. The residue was subjected to column chromatography (0 to 5% MeOH (NH 3 ) in DCM). The isolated residue was found to still contain DMSO and was partitioned between DCM (500 mL) and water (250 mL). The aqueous phase was extracted an additional five times until the product was completely extracted. The organic phases were combined and the solvent was removed under reduced pressure to give (4R,4aS,7aR,12bS)-4a-hydroxy-3-methyl-7-oxo-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenethyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (compound-15); 1.2 g, 2.3 mmol, 33 % yield).

[0116] To a solution of crude compound-15 (52 g) in acetic acid (55 mL) was added zinc powder (3.03 g, 45.8 mmol), followed by concentrated aqueous HCl (2 mL). The reaction was heated to 90°C for 2 hours. The reaction mixture was allowed to cool to 60°C and filtered. The zinc residue was washed with additional acetic acid (30 mL). The combined acetic acid solutions were concentrated under reduced pressure. The residue was basified with ammonium hydroxide solution (28%) and extracted with Me-THF (2 x 250 mL). The organic phase was dried (MgSO 4 ), filtered and the solvent was removed under reduced pressure. The crude product was subjected to column chromatography (0 to 5% MeOH (NH3) in DCM) followed by prep-HPLC to give compound 10 (4,14-dihydroxy-N-{2-[4-(2-hydroxypyridin-4-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide) (378 mg, 0.72 mmol, 31% yield) as a white solid; LC/MS 528 (M+H)<+>; NMR(DMSO-D6): 533-20-7_1H-3.jdf: 1.45 (1H, d), 1.58-2.10 (4H), 1.8 (3H, s), 2.19-2.38 (1H, m), 2.40-3.10 (10H, m), 3.78 (1H, d), 4.68 (1H, bs), 6.46 (1H, dd), 6.53 (1H, s), 6.61 (1H, d), 7.31 (2H, d), 7.39 (1H, d), 7.53 (1H, d), 7.60 (2H, d), 8.96 (1H, bs).

Example 11: Synthesis of compound 7

[0117]

[0118] To an ice-cold solution of (4a'S,7a'R)-9'-(benzyloxy)-3'-methyl-1',2',3',4',5',6'-hexahydro-4a'H-spiro[1,3-dioxolane-2,7'-[4,12]methano[1]benzofuro[3,2-e]isoquinoline]-4a'-ol (10 g, 23 mmol) in DMF (100 mL) was added portionwise sodium hydride (4.6 g, 115 mmol). The mixture was stirred cold for 2 hours, then methyl iodide (2.9 mL, 45.9 mmol) was added in one portion. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water (500 mL) and extracted into DCM (2 x 500 mL). The organic layer was washed with water (3 x 300 mL) and brine (300 mL), dried (MgSO4), filtered and concentrated to give the crude product. The product was purified by chromatography on silica gel (eluting with 0-10% ammonia/methanol in DCM) to give the product (4R,4aS,7aR,12bS)-9-(benzyloxy)-4a-methoxy-3-methyl-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12methanobenzofuro[3,2-e]isoquinoline-7,2'-[1,3]dioxolane] as a viscous yellow oil (7.3 g, 71% yield).

[0119] To a solution of (4R,4aS,7aR,12bS)-9-(benzyloxy)-4a-methoxy-3-methyl-1,2,3,4,4a,5,6,7aoctahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2'-[1,3]dioxolane] (7.3 g, 16.2 mmol) in MeOH (75 mL) was added conc. HCl (50 mL). The mixture was refluxed for 5 hours, then cooled with an ice bath. Concentrated ammonia (25%) was added until pH 8 was reached. The mixture was concentrated and the residue was stirred with 10% MeOH/DCM (1 L) overnight. The mixture was filtered and the liquids were concentrated to give (4R,4aS,7aR,12bS)-9-hydroxy-4a-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one as a dark red oil (5.3 g, quantitative yield).

[0120] A mixture of (4R,4aS,7aR,12bS)-9-hydroxy-4a-methoxy-3-methyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-7(7aH)-one (5.1 g, 16.2 mmol), N-Phenylbis(trifluoromethanesulfonamide) (6 g, 16.7 mmol), triethylamine (6.8 mL, 48.5 mmol) and DCM (80 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the crude product still containing the triflate reagent. This was dissolved in a 4:1 mixture of ethyl acetate/hexane (200 mL) and washed with water (5 x 150 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give the product (4R,4aS,7aR,12bS)-4a-methoxy-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-9-yl trifluoromethanesulfonate as a brown oil. (5.9 g, 81 % yield). Compounds 7 and 16 were synthesized from the above-mentioned intermediate in a similar procedure as in the synthesis of compounds 10 and 15.

Example 12: Synthesis of compound 11

[0121]

[0122] A mixture of (5a)-N-[2-(4-bromophenyl)ethyl]-14-hydroxy-17-methyl-6-oxo-4,5-epoxymorphinan-3-carboxamide (1) (10 g, 19.6 mmol), denatured ethanol (300 mL), zinc powder (28 g, 0.43 mol) and ammonium chloride (34.5 g, 0.65 mol) was heated at reflux for 30 min and then cooled to ~40°C. The reaction mixture was filtered through celite and washed with denatured ethanol (300 mL, 40°C). Volatiles were removed under vacuum and the residue was partitioned between dichloromethane (200 mL) and 2% aqueous ammonia (300 mL). The aqueous phase was further extracted with dichloromethane (2x200mL) and the combined organics were dried over MgSO4 and evaporated. The residue was purified on silica eluting with dichloromethane/methanol (95:5 to 9:1) to give N-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphinan-3-carboxamide (2) (7.95 g, 79%) as a brown solid.

[0123] To a degassed mixture of ethanol and water (4:1, 20 mL) was added 2-methoxypyrimidin-5-ylboronic acid (0.67 g, 4.4 mmol), Na2CO3 (1.24 g, 11.7 mmol) and N-[2-(4-bromophenyl)ethyl]-4,14-dihydroxy-17-methyl-6-oxomorphin-3-carboxamide (2) (1.5 g, 2.9 mmol). The reaction mixture was further degassed and then Pd(PPh3)4 (0.32 g, 0.3 mmol) was added. The reaction mixture was heated in a microwave reactor at 120°C for 25 minutes. and cooled. The reaction mixture was diluted with ethyl acetate (50mL) and washed with 1:1 saline/water (3x35mL). The organic phase was dried over MgSO4, filtered and evaporated. The resulting residue was further purified on silica eluting with dichloromethane/methanol (9:1) to give 4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide (3) (0.50g, 32%) as a yellow foam.

[0124] A mixture of 4,14-dihydroxy-N-{2-[4-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-17-methyl-6-oxomorphinan-3-carboxamide (3) (0.5 g, 0.9 mmol) and pyridine hydrochloride (5 mL) was heated at 150°C for 6 hours. The reaction mixture was cooled, basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x40 mL). The aqueous phase was filtered and the collected brown solid was combined with the organic residue from the wash and evaporated to dryness. The residue was purified on silica eluting with dichloromethane/methanol (9:1) to dichloromethane/16% NH3 in methanol (9:1) to give 4,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl]ethyl}morphinan-3-carboxamide (RDC6139). (0.15g) as a white solid. This was dissolved in dichloromethane/methanol (3:1, 20 mL) and maleic acid (32 mg, 1 eq.) was added. The reaction mixture was stirred for 4 hours and then the leachables were removed under vacuum at 40°C. The residue was freeze-dried from water to give compound 11 4,14-dihydroxy-17-methyl-6-oxo-N-{2-[4-(2-oxo-1,2-dihydropyrimidin-5-yl)phenyl]ethyl}morphinan-3-carboxamide maleate salt (0.17g, 98%) as a white solid; LC/MS 529 (M+H) + ; NMR(D2O): 1.15-1.21 (4H, m), 1.49-1.60 (1H, m), 1.65-1.90 (3H, m), 2.10-2.22 (1H, m), 2.29-2.41 (1H, m), 2.50-2.72 (5H, m), 2.90-3.00 (1H, m), 3.18-3.40 (3H, m), 3.45-3.60 (2H, m), 6.04 (2H, s), 6.95-7.05 (4H, m), 7.26 (1H, m), 8.11 (2H, bs).

Example 13: Synthesis of compound 5

[0125]

[0126] A mixture of hydromorphone HCl (100 g, 0.31 mol), N-Phenylbis(trifluoromethanesulfonamide) (114 g, 0.32 mol), diisopropylethylamine (215 mL, 1.24 mol) and DCM (2 L) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the crude product still containing the triflate reagent. This was dissolved in 4:1 ethyl acetate/hexane (1 L) and washed with water (6 x 1 L). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to give the product (4R,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-9-yl trifluoromethanesulfonate as a white solid (120 g, 93 % yield). (4R,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-9-yl trifluoromethanesulfonate (5 g, 11.98 mmol) was stirred in degassed DMSO (80 mL). N-Hydroxysuccinimide (2.76 g, 23.96 mmol) was added, followed by triethylamine (3.3 mL, 23.96 mmol), palladium acetate (0.27 g, 1.2 mmol) and xanthophos (0.69 g, 1.2 mmol). The reaction mixture was stirred at 70°C under CO overnight. The mixture was allowed to return to room temperature before the addition of 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (3.2 g, 11.98 mmol) and triethylamine (3.3 mL, 23.96 mmol). The reaction was stirred for 5 hours before removing the DMSO under reduced pressure. The residue was mixed with DCM and filtered to give a brown solid, which was used as is for the next step. (4R,7aR,12bS)-N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phe3nethyl)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carboxamide (6 g, 79% crude yield).

[0127] In a solution of crude (4R,7aR,12bS)-N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenethyl)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinoline-9-carboxamide (5 g) in acetic acid (200 mL) was added zinc powder (12.6 g, 190 mmol), followed by concentrated aqueous HCl (7.5 mL). The reaction was heated to 90°C for 2.5 hours. More zinc powder (47.6 g, 717 mmol) was added in portions over 24 hours. After cooling to room temperature, the zinc salts were removed by filtration and washed with additional acetic acid (80 mL). The combined acetic acid solutions were concentrated under reduced pressure. The residue was basified with ammonium hydroxide solution (28%) and extracted with Me-THF (3 x 500 mL). The organic phase was dried (MgSO 4 ), filtered and the solvent was removed under reduced pressure. The crude product was purified by prep-HPLC to give compound 5 (4bS,9R)-N-(4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenethyl)-4-hydroxy-11-methyl-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethane)phenanthrene-3-carboxamide as a white solid. solid (0.89 g, 18 % yield); LC/MS 529 (M+H) + ; NMR(DMSO-D6): 1.25-1.50 (1H, m), 1.55-1.89 (4H, m), 1.98 (1H, d), 2.05-3.00 (7H, m), 3.20-3.60 (6H, m), 4.01 (1H, d), 6.61 (1H, d), 7.19 (2H, d), 7.45 (2H, d), 7.50-7.64 (4H, m), 8.90 (1H, bs), 11.20 (1H, bs), 13.86 (1H, bs).

Example 14: Synthesis of compound 2

[0128]

[0129] A mixture of noroxymorphone (40.0 g, 139.2 mmol), potassium hydrogen carbonate (27.9 g, 278.7 mmol), and (2-bromoethyl)benzene (47.6 mL, 348.0 mmol) in DMF (750 mL) was heated at 70 °C overnight. The reaction mixture was cooled to room temperature, filtered and concentrated under reduced pressure. The residue was partitioned between ethyl acetate (800 mL) and water (500 mL). The organic phase was dried (MgSO 4 ), filtered and the solvent was removed under reduced pressure. The crude residue was mixed with a mixture of 2N aqueous HCl (500 mL) and ethyl acetate (500 mL). The resulting precipitate was isolated by filtration, washed with water and dried (50°C) to give (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one hydrochloride (46.6 g, 109.0 mmol, 78 % yield).

[0130] To a suspension of (4R,4aS,7aR,12bS)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one hydrochloride (46.6 g, 109.0 mmol) in DCM (1 L) was added. diisopropylethylamine (76 mL, 435.9 mmol), followed by N-phenylbis(trifluoromethanesulfonamide) (40.1 g, 112.2 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in 4:1 ethyl acetate:hexane (500 mL total). The organic phase was washed with water (6 x 500 mL) and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave (4R,4aS,7aR,12bS)-4a-hydroxy-7-oxo-3-phenethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-9-yl trifluoromethanesulfonate (57.0 g, 109.0 mmol, 100 % yield) as orange oil.

[0131] (4R,4aS,7aR,12bS)-4a-hydroxy-7-oxo-3-phenethyl-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanebenzofuro[3,2-e]isoquinolin-9-yl trifluoromethanesulfonate (6.26 g, 12.0 mmol) was stirred in degassed DMSO. (80 mL). N-hydroxysuccinimide (2.76 g, 24.0 mmol) was added, followed by triethylamine (3.34 mL, 24.0 mmol), palladium acetate (269 mg, 1.2 mmol) and xanthophos (693 mg, 1.2 mmol). The reaction mixture was stirred at 70°C under CO overnight. The mixture was allowed to return to room temperature before the addition of 5-(4-(2-aminoethyl)phenyl)pyrimidine-2,4(1H,3H)-dione hydrochloride (2.0g, 8.0 mmol) and triethylamine (1.7 mL, 12.0 mmol). The reaction was stirred for 3 hours before removing the DMSO under reduced pressure. The residue was subjected to column chromatography (0 to 3% MeOH(NH3) in DCM). The organic phases were combined and the solvent was removed under reduced pressure to give (5a)-N-{2-[4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-14-hydroxy-6-oxo-17-(2-phenylethyl)-4,5-epoxymorphinan-3-carboxamide (Compound-18; 4.7 g, 7.4 mmol, 62% yield).

Zinc powder was added to a solution of N-{2-[4-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-14-hydroxy-6-oxo-17-(2-phenylethyl)-4,5-epoxymorphinan-3-carboxamide (Compound-18) (4.7 g, 7.4 mmol) in acetic acid (200 mL). (14.6 g, 223 mmol), followed by concentrated aqueous HCl (8 mL). The reaction was heated to 90°C for 1 hour, after which more zinc powder (14.6 g) was added. The reaction was maintained at the same temperature for an additional 2 hours. The reaction mixture was allowed to cool and filtered. The zinc residue was washed with additional acetic acid (100 mL). The combined acetic acid solutions were concentrated under reduced pressure. The residue was basified with ammonium hydroxide solution (28%) and the precipitated solid was isolated by filtration. The precipitate was washed with water and dried overnight in a desiccator. The material was purified by prep-HPLC to give compound 2 N -{2-[4-(2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]ethyl}-4,14-dihydroxy-6-oxo-17-(2-phenylethyl)morphinan-3-carboxamide (1.17 g, 1.85 mmol, 25% yield) as a white solid; LC/MS 635 (M+H)+; NMR(DMSO-D6): 502-133-9_1H-3.jdf: 1.40-1.50 (1H, m), 1.60-1.70 (2H, m), 1.78-1.95 (3H, m), 2.50-2.58 (2H, m), 2.59-2.67 (3H, m), 2.68-2.77 (3H, m), 2.78-2.90 (4H, m), 2.91-3.20 (2H, m), 3.77 (1H, d), 4.30 (1H, s), 6.61 (1H, d), 7.10-7.32 (7H, m), 7.44 (2H, d), 7.54 (2H, d), 8.91 (1H, t), 11.07 (1H, bs), 11.20 (1H, bs), 13.94 (1H, bs).

Example 15: Determination of binding affinities for mu, delta and kappa receptors

[0133] Receptor binding (in vitro assay) Ki (binding affinity) for μ-, δ- and κ-receptors was determined with a previously described procedure using a competitive displacement assay (Neumeyer, 2003). Membrane protein from CHO (Chinese hamster ovary) cells stably expressing one type of cloned human opioid receptor was incubated with 12 different concentrations of compounds in the presence of 0.25 nM [3H]DAMGO, 0.2 nM [3H]naltrindole, or 1 nM [3H]U69,593 in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5 at 25°C. Incubation times of 60 min were used for [3H]DAMGO and [3H]U69,593. Due to the slower binding of [3H]naltrindole to the receptor, a 3 hour incubation was used with this radioligand. Samples incubated with [3H]naltrindole also contained 10 mM MgCl2 and 0.5 mM phenylmethylsulfonyl fluoride. Nonspecific binding was measured by inclusion of 10 μM naloxone. Binding was completed by filtering the samples through Schleicher & Schuell No. 32 glass fiber filters using a Brandel 48-chamber cell harvester. Filters were then washed three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and counted in 2 mL of Ecoscint A scintillation fluid. For binding of [3H]naltrindole and [3H]U69,593, filters were soaked in 0.1% polyethyleneimine for at least 60 min before use. IC50 values will be calculated using a least squares approximation by log-probit analysis. K values of unlabeled compounds were calculated from the equation Ki= (IC50)/1 S where S = (concentration of radioligand)/(Kd of radioligand) (Cheng and Prusoff, 1973).

Example 16: Functional activity (GTPγS binding)

[0134] The [<35>S]GTPγS assay measures the functional properties of compounds by quantifying the level of G-protein activation following agonist binding in studies using stably transfected cells, and is considered a measure of compound efficacy. Membranes from CHO (Chinese Hamster Ovary) cells stably expressing the cloned human Mu opioid receptor were used in the experiments. In a final volume of 0.5 mL, 12 different concentrations of each test compound were incubated with 7.5 μg of CHO cell membranes stably expressing the human μ opioid receptor. The assay buffer consisted of 50 mM Tris-HCl, pH 7.4, 3 mM MgCl2, 0.2 mM EGTA, 3 μM GDP, and 100 mM NaCl. The final concentration of [<35>S]GTPγS was 0.080 nM. Nonspecific binding was measured by inclusion of 10 μM GTPγS. Bonding was initiated by adding membranes. After incubation for 60 min at 30°C, the samples were filtered through Schleicher & Schuell No. 32 glass fiber filters. Filters were washed three times with cold 50 mM Tris-HCl, pH 7.5, and counted in 2 mL of Ecoscint scintillation fluid. Results are mean Emax and EC50 values ± S.E.M. To calculate Emax values, the basal binding of [<35>S]GTPγS was set to 0%, and the 100% binding level of [<35>S]GTPγS was set to the maximal binding achieved with DAMGO. The compounds in Table D show [<35>S]GTPγS binding EC50 values between 1.3 nM and 300 nM with Emax values between 70% and 140%.

Example 17: In vivo behavioral studies

[0135] Groups of mice (n=5 per group; >60 days; 20-25 grams weight) were dosed with vehicle (0.9% sterile saline) or test compounds (10 mg/kg free base, SC) 30 minutes before the first observation period. The appearance of Straub's tail, piloerection, hyperlocomotion, hypolocomotion, cage circling, sedation, breathing abnormalities, diuresis, convulsive activity and the occurrence of deaths were recorded at 0.5, 1, 2, 4, 6 and 24 hours after dosing.

[0136] The data below show peripheral limitation for a series of compounds. This was tested with our clinical observational assay where mice were injected subcutaneously with 10 mg/kg of the drug and behaviors were recorded after 24 hours. At 10 mg/kg SC, both morphine (compound-A) and compound-B showed severe effects reflecting mu brain agonism, with mortality noted in the compound-B group. Behavioral effects and mortality were not observed with the tested heteroaryl compounds. The binding affinities of compounds 1-11 are given in Table D.

Table D

Example 18: CFA-induced weight-bearing deficits in rats

[0137] The animals were habituated to the load bearing test apparatus for days before the start of the experiment. On day 0, rats were tested in the load-bearing apparatus to measure baseline load-bearing of untreated hind paws. After baseline testing, animals were intraplantarly injected with complete Freund's adjuvant (CFA). Using a syringe with a locking hub and a 25G needle, rats were injected intraplantarly with 100 μL of 100% CFA (1.0mg/ml) in the hind left paw while under light anesthesia with isofluorane. No treatment was applied to the right, hind, contralateral paw.

[0138] Treatment with morphine or compound 4 (Intra-articular) was given after the onset of arthritis in CFA-treated rats (Day 1). Intra-plantar administration of the test compound was performed while the animals were under light anesthesia (3%) with isofluorane using a 0.3ml insulin syringe. The amount of anesthesia given to the animal during the administration of the test compound was limited to a very short duration, so as not to interfere with the measurement of load bearing at the 5 minute time point. On day 1 (24 h post-CFA), rats were tested in the weight-bearing apparatus to measure CFA-induced changes in weight-bearing. After testing, animals were intraplantarly injected with the test compound (morphine or compound 4) in a total volume of 50 μl containing doses of 3, 10, or 100 μg. The inhibitory effect of naloxone on the analgesic effects of compound 4 and morphine (10μg/paw) was tested by simultaneous intra-plantar administration of 75µg naloxone methiodide, a peripherally restricted opioid antagonist. After administration of the test compound, the animals were tested again in the load bearing apparatus at the following time points: 5, 15, 30, 60 and 120 minutes after administration of the test compound. Animals were tested again on day 2 (post-CFA) if there was a significant change in CFA-induced load bearing at the 120-min time point on day 1.

[0139] Administration of (intra-plantar) compound 4 produced a dose-dependent reversal of CFA-induced weight-bearing deficits at 3, 10 and 30 μg/paw. The analgesic effects of compound 4 were similar to those observed with morphine (FIG. 1 and 2). The analgesic effects of compound 4 or morphine (10μg/paw) were significantly inhibited by simultaneous intra-plantar administration of 75µg naloxone methiodide, a peripherally restricted opioid antagonist. Blockade of analgesia by intraplantar administration of naloxone metiodide suggests peripheral analgesic effects of compound 4 and morphine.

Example 19: Rat Model of Centrally Mediated Hot Plate Analgesia

[0140] The potential antinociceptive properties of subcutaneous (SC) administration of compound 4 were evaluated at doses of 10, 30 and 100 mg/kg in the hot plate antinociception test in rats. Morphine (used as a reference compound) produced maximal (60 sec.) antinociception when administered SC at 7.5 mg/kg (shown here, and in previous in-house experiments).

[0141] Rats were tested for baseline hot plate responding (latency time to paw on a hot plate set to 52.5°C) immediately prior to dosing with compound 4 or morphine (7.5 mg/kg) by SC injection. Rats were then tested on the hot plate 5, 30, 60, 120, 240, and 360 minutes later. The amount of time it took them to put down their hind paw was measured and considered the response latency. Mean and SEM response latencies for each experimental group were calculated and a line plotting mean hot plate latency versus time was generated using GraphPad Prism. An increase in mean response latency above baseline after test compound administration is indicative of an antinociceptive effect.

[0142] Compound 4 was significantly less active than morphine on the hot plate, with submaximal efficacy at the highest dose tested (100 mg/kg), suggesting significant peripheral limitation of compound 4 (FIG. 3).

Example 20: Formalin pain model

[0143] Non-starved male Harlan rats were assigned to treatment groups according to a randomized block study design to balance for test chamber and time of day, and test day (if applicable). Each rat received vehicle or test compound subcutaneously and then placed in its assigned test chamber and acclimatized for 25-30 minutes with the chamber door open. Data were not collected during this period. After the acclimatization period, each rat was removed individually starting with chamber 1, and dosed with 5% formalin subcutaneously in the plantar surface of the right hind paw (formalin was prepared from 37% stock solution, diluted to 5% with saline).

[0144] Data collection began when the first rat was replaced in chamber 1 and the chamber door was closed and locked (skipped the 1 minute acclimation screen in the software). The number of events (also defined as "number of seconds"), defined as the number of 1-second segments with a change in dynamic force that exceeded an empirically determined threshold value (a value of arbitrary load units, which visually corresponded to quietly breathing or sniffing rats), was calculated at 5-minute intervals. In control rats, the number of events first increases within 5 minutes and then decreases during the next 5 minutes (quiet phase) after formalin administration (Phase I, or early phase, of the formalin test), then increases again during the next 35 minutes (Phase II, or late phase) of the formalin test. Formalin-induced movements detected by the system include licking and avoidance of the affected paw as well as jumping and turning.

[0145] To summarize the design for the analysis of dose-response curves or screens in the formalin test, the total number of events during the first 5 minutes after formalin administration was considered as phase I (early phase), and the total number of events for minutes 11 to 35 after formalin was considered as phase II (late phase). Data were analyzed using 1-way ANOVA, and comparisons of drug treatment groups were compared with control groups using appropriate, statistically-guided tests—most commonly Dunnett's for dose-response curves and Student's t-test for two-group comparisons (ie, vehicle vs. positive control)—using JMP statistical software (SAS Institute Inc, Cary, NC). Data are expressed as mean values ± SEM. ED50 was calculated using GraphPad Prism software.

[0146] Subcutaneous administration of compound 4 produced a dose-dependent reversal of formalin-induced events. The antinociceptive (analgesic) effects of compound 4 (ED503.62 mg/kg) were similar to morphine (ED502.4 mg/kg). As shown in FIG. 4, a 10 mg/kg dose of morphine completely attenuates the early and late phase effects of formalin, suggesting both a centrally mediated (early phase) and a peripherally mediated (late phase) effect on antinociception (analgesia). A much stronger effect of compound 4 exists in the late phase than the early phase, suggesting a preferential, peripherally mediated effect on peripheral inflammatory pain.

Example 21: Acetic acid-induced writhing model of inflammatory pain

[0147] Intraperitoneal administration of morphine dose-dependently blocked writhing induced by intraperitoneal administration of 1% acetic acid in mice with an ED50 of 0.25 mg/kg. The dose-response of the analgesic effects of intraperitoneal administration of compound 4 was measured in the 1% acetic acid-induced writhing assay in mice.

[0148] Groups of mice (n=10 per group) were dosed intraperitoneally with vehicle control (0.9% saline), morphine, or compound 4, 30 minutes before testing followed by a dose of 1% acetic acid 5 minutes before testing. The number of twists is counted for 15 minutes (3 consecutive 5-minute time sections). For a movement to be considered a twist, two or more of the following criteria are met:

• visible concave curvature of the spine (designated by the term pelvic tilt) – dose movement of the caudal region of the spine that creates a concave shape when viewed from the side; moving the hips to either the left or the right; or both.

• Greater concave curvature of the spine was considered vertical twisting.

• The abdomen made an effort to lower itself to the ground.

• Hind legs, body, or both are stretched back and extended.

• The tail is abruptly displaced upward from the base (not typically occurring separately from the pelvic tilt).

• In the case of a chain of multiple twists, the end of a particular twist is determined when the mouse has returned to the "normal" position before another twist. "Normal" position is defined as movements opposite to those mentioned in the previous text (eg convex curvature of the spine, legs not stretched, abdomen not lowered, tail in a straight or relaxed position, etc.).

[0149] The total number of twists during the 15-minute test session was used to analyze all data. All data were transformed using GraphPad Prism to % change from daily vehicle control for analysis based on the number of writhes produced by the vehicle, saline control group (% change = # of writhes in the test group / mean # of writhes in the once-daily vehicle control group * 100). ED50 of % change from vehicle control was calculated for morphine and compound 4 using GraphPad Prism software.

[0150] As shown in FIG. 5, (intraperitoneal) administration of compound 4 blocked acetic acid-induced writhing in a dose-dependent manner with a calculated ED50 of 0.7 mg/kg.

Claims (21)

Patent claims 1. A compound of formula I, or a pharmaceutically acceptable ester thereof: where: u is 0, 1 or 2; t is 0, 1, 2, 3, 4, 5, 6, or 7; X is S or O; R 1 is selected from aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; each R2, R3, R4, R6, R8, and R11 is independently selected from the absence of hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; or alternatively R 2 and R 3 together with the carbon to which they are attached to form a C=X group; alternatively, two R11 groups together with the carbon atom to which they are attached form a C=X or C=CH2 group; wherein each R 20 and R 21 are independently selected from hydrogen, halogen, alkyl, substituted alkyl, aryl or substituted aryl; R 7 is hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; R 9 is selected from hydrogen, aliphatic, substituted aliphatic, aryl, substituted aryl, heterocyclyl or substituted heterocyclyl; and R10 is selected from substituted aryl in Table A: TABLE A where s is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4, 5, 6 or 7; q is 0, 1, 2, 3, 4 or 5; each R100, R101, R102, R103, R104, and R105 is independently selected from hydrogen, halogen, -OR20, -SR20, -NR20R21, -C(O)R20, -C(O)OR20, -C(O)NR20R21, -N(R20)C(O)R21, -CF3, -CN, -NO2, -N3, acyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino, substituted dialkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkylsulfonyl, optionally substituted aliphatic, optionally substituted aryl, heterocyclyl or substituted heterocyclyl; wherein the term "substituted" means the replacement of one or more hydrogen radicals in a given structure with a radical of an indicated substituent selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkyl, aminocarbonyl, alkylaminocarbonyl, Arylaminocarbonyl, Alkoxycarbonyl, Aryloxycarbonyl, Haloalkyl, Amino, Trifluoromethyl, Cyano, Nitro, Alkylamino, Arylamino, Alkylaminoalkyl, Arylaminoalkyl, Aminoalkylamino, Hydroxy, Alkoxyalkyl, Carboxyalkyl, Alkoxycarbonylalkyl, Aminocarbonylalkyl, Acyl, Aralkoxycarbonyl, Carboxylic acid, Sulfonic acid, Sulfonyl, Phosphonic acid, Aryl, heteroaryl, heterocyclic and aliphatic. 2. The compound according to claim 1, characterized in that R<7> is hydrogen. 3. The compound according to claim 1 or 2, characterized in that u is 1. 4. A compound according to any of the preceding claims wherein X is oxygen. 5. A compound according to claim 1, characterized in that the compound is a compound of formula V or a pharmaceutically acceptable ester thereof: 6. A compound according to any of the preceding claims characterized in that R1 is selected from -(CH2)a-c-C3H5, -(CH2)a-c-C4H7, -(CH2)a-c-C5H9, -(CH2)a-CH=CH2, -CH3, -CH2-CH2-Phenyl or -(CH2)a-CH=C(CH3)2where a is independently 0, 1, 2 or 3. 7. A compound according to any of the preceding claims wherein R4 is hydrogen or hydroxy. 8. A compound according to claim 1 selected from Table B: TABLE B 9. A compound according to any one of claims 1 to 4 or 6 to 8, characterized in that R 9 is hydrogen. 10. A compound according to any one of the preceding claims, characterized in that R10 is selected from: 11. A compound according to claim 1 selected from Table C: TABLE C 12. A compound according to any of claims 1 to 11 for use in a method of treating a disease or disorder selected from pain, drug addiction, opiate addiction, alcohol addiction, nicotine addiction, cocaine addiction, post-operative ileus, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, cough and hyperalgesia. 13. The compound for use according to claim 12 wherein said disease or disorder is pain. 14. The compound for use according to claim 13 wherein said pain is selected from inflammatory pain, centrally mediated pain, peripherally mediated pain, visceral pain, structural pain, cancer pain, pain associated with soft tissue injury, pain associated with progressive disease, neuropathic pain and acute pain from acute injury, acute pain from trauma, acute pain from surgery, chronic headache pain, chronic pain from neuropathic conditions, chronic post-stroke pain and chronic migraine pain. 15. The compound for use according to claim 13 characterized in that said pain is associated with osteoarthritis, rheumatoid arthritis, fibromyalgia, migraine, headache, toothache, burns, sunburn, snake bite, spider bite, insect sting, neurogenic bladder, benign prostatic hypertrophy, interstitial cystitis, rhinitis, contact dermatitis/hypersensitivity, itching, eczema, pharyngitis, mucositis, enteritis, cellulitis, causalgia, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, post-amputation stump pain, phantom limb pain, post-operative ileus, cholecystitis, post-mastectomy pain syndrome, oral neuropathic pain, Charcot pain, reflex sympathetic dystrophy, Guillain-Barre syndrome, paresthetic meralgia, burning mouth syndrome, post-herpetic neuralgia, trigeminal neuralgia, cluster headache, migraine headache, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migraine neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, Vidian neuralgia, inflammatory disease, irritable bowel syndrome intestines, sinus headache, tension headache, childbirth, childbirth, menstrual pain and cancer. 16. The compound for use according to claim 13, characterized in that said pain is associated with arthritis. 17. The compound for use according to claim 16 characterized in that said arthritis is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, juvenile arthritis, scapulohumeral periarthritis. 18. Compound for use according to claim 12 characterized in that said disease or disorder is selected from drug addiction, opiate addiction, alcohol addiction, nicotine addiction, cocaine addiction, post-operative ileus, pruritis, diarrhea, irritable bowel syndrome, gastrointestinal motility disorder, obesity, respiratory depression, convulsions, cough, hyperalgesia. 19. The compound for use according to claim 18, wherein the condition or disease is gastrointestinal dysfunction, or ileus. 20. A compound for use in a method for treating or preventing an opioid-related side effect, wherein said method comprises the step of: administering to a patient in need thereof, a composition comprising an effective amount of a compound according to any one of claims 1-11. 21. The compound for use according to claim 20, wherein the side effect is selected from the group consisting of constipation, opioid-induced bowel dysfunction, nausea, vomiting, and combinations thereof.